Suetterlin Karen, Law Sinead, Arnold William David
AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle upon Tyne, United Kingdom.
Front Neurol. 2024 Dec 23;15:1507485. doi: 10.3389/fneur.2024.1507485. eCollection 2024.
In Periodic Paralysis (PP), a rare inherited condition caused by mutation in skeletal muscle ion channels, the phenotype changes with age, transitioning from the episodic attacks of weakness that give the condition its name, to a more degenerative phenotype of permanent progressive weakness and myopathy. This leads to disability and reduced quality of life. Neither the cause of this phenotype transition, nor why it occurs around the age of 40 is known. However, 40 is also the age of onset of 'normal' age-related physiological decline when we consider (a) muscle mass and strength (b) physical function at the world class level and (c) age-related mitochondrial dysfunction. Elevated Na, mitochondrial dysfunction and sarcoplasmic Ca leak via the skeletal muscle ryanodine receptor (RyR1) have been implicated in both periodic paralysis myopathy and skeletal muscle ageing. We suggest this combination may trigger a negative spiral ultimately leading to progressive muscle failure. Understanding the interaction between ageing physiology and disease phenotype will provide a window into the healthy ageing process but also help understand how, and why PP phenotype changes with age. Understanding the mechanism underlying PP phenotype-transition and its link with ageing physiology, not only has the potential to identify the first disease modifying therapies for PP, but also to identify novel and potentially tractable mechanisms that contribute to sarcopenia, the pathological loss of muscle mass and function with age.
在周期性麻痹（PP）中，这是一种由骨骼肌离子通道突变引起的罕见遗传性疾病，其表型会随年龄变化，从以发作性肌无力为特征（该疾病即因此得名）转变为更为退行性的表型，即永久性进行性肌无力和肌病。这会导致残疾并降低生活质量。目前既不清楚这种表型转变的原因，也不知道为何它会在40岁左右发生。然而，当我们考虑（a）肌肉质量和力量、（b）世界级水平的身体功能以及（c）与年龄相关的线粒体功能障碍时，40岁也是“正常”的与年龄相关的生理衰退的起始年龄。高钠、线粒体功能障碍以及通过骨骼肌兰尼碱受体（RyR1）的肌浆钙泄漏已被认为与周期性麻痹性肌病和骨骼肌衰老都有关联。我们认为这种组合可能引发一个恶性循环，最终导致进行性肌肉衰竭。了解衰老生理学与疾病表型之间的相互作用，不仅将为健康衰老过程提供一个窗口，还将有助于理解PP表型如何以及为何随年龄变化。了解PP表型转变的潜在机制及其与衰老生理学的联系，不仅有可能确定针对PP的首个疾病修饰疗法，还能识别出导致肌肉减少症（即随着年龄增长肌肉质量和功能的病理性丧失）的新的且可能易于处理的机制。
